HPK1

-- New development candidate, NTX-452, a non-covalent WRN inhibitor, demonstrated significant tumor regression and complete responses at low oral doses in MSI-H tumor models refractory to immunotherapy and chemotherapy -- -- Company plans to initiate clinical trial of NTX-452 in first half of 2025 -- BOSTON--(BUSINESS WIRE)-- Nimbus Therapeutics , LLC (“Nimbus Therapeutics” or “Nimbus”), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, announced that it is presenting preclinical data on its new development candidate, NTX-452, a novel Werner syndrome helicase (WRN) inhibitor, at the 36 th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, taking place October 23-25, 2024 in Barcelona, Spain. WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of defective mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric and endometrial cancers. Inhibition of WRN activity has the potential to induce synthetic lethality in MSI-high (MSI-H) tumors. Using a structure-based drug design approach, Nimbus developed highly potent and selective covalent and non-covalent inhibitors of WRN, and has selected a novel non-covalent inhibitor, NTX-452, as the clinical candidate. In a poster (abstract #356) titled “Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors,” Nimbus is presenting new data from preclinical assays and several tumor models that support the potential of the company’s non-covalent WRN inhibitor as a treatment for MSI-H tumors. Key findings from the preclinical studies include: NTX-452 demonstrated potent and selective inhibition of WRN activity with favorable drug-like properties. The compound showed synthetic lethality in MSI-H tumor cells, triggering a DNA damage response that suppressed cell viability and promoted cell death. Treatment with NTX-452 at low doses in vivo exhibited a robust pharmacodynamic response, resulting in tumor regression across multiple MSI-H cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor models, including established models for colorectal, gastric and endometrial cancers. Significant tumor regression and complete responses were observed at low oral doses in MSI-H models refractory to immunotherapy and chemotherapy. “These compelling preclinical results for NTX-452 further highlight the significant potential of our WRN inhibitor as a promising therapeutic approach for patients with MSI-H tumors, many of whom fail to respond to or eventually relapse with current standard of care therapies including immune checkpoint inhibitors,” said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus. “Our novel non-covalent approach to WRN inhibition, coupled with the robust efficacy demonstrated across diverse tumor types and treatment settings, positions our program for potential best-in-class status. We are particularly encouraged by the low doses required to achieve robust anti-tumor activity in preclinical models, which may translate to an improved benefit-risk pro the clinic.” The preclinical pro NTX-452 suggests several potential advantages in the treatment of MSI-H tumors, including: The non-covalent mechanism may offer more durable on-target activity, and a greater safety window compared to covalent inhibitors. High potency and favorable pharmacokinetic properties indicate the potential for target levels of efficacy at lower doses. Broad efficacy across treatment-naïve, chemotherapy-pretreated, and immunotherapy-pretreated models suggests potential utility in both early-stage and advanced disease settings. Activity in multiple MSI-H tumor types, including those with diverse genetic alterations, indicates potential broad applicability across dMMR/MSI-H cancers. Nimbus is advancing NTX-452 with plans to enter the clinic in the first half of 2025. About Nimbus Therapeutics Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches. Nimbus’ pipeline includes a clinical-stage HPK1 inhibitor for the treatment of cancer (NCT05128487), as well as a diverse portfolio of preclinical programs focused on cancer, including the WRN program, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit . Contacts Media Cindy Fung, PhD Nimbus Therapeutics cindy.fung@nimbustx.com

Genentech has entered into an agreement with Regor Pharmaceuticals to acquire its next-generation CDK inhibitors for the treatment of breast cancer. The deal includes an upfront payment of $850 million, with additional payments contingent on the achievement of development, regulatory, and commercial milestones. Genentech will handle clinical development, manufacturing, and commercialization worldwide. Regor will continue to manage two ongoing phase 1 trials to their completion and will focus on advancing other assets in oncology, metabolic diseases, and autoimmune disorders that are not part of this acquisition. In addition to its CDK inhibitor portfolio, Regor has other leading assets including RGT-075, a GLP-1 receptor agonist with potential applications for obesity and related conditions, and RGT-419B, a CDK4 inhibitor showing promise for treating advanced breast cancer resistant to standard therapies. The company also explores immune-modulatory drugs like HPK1 inhibitors for cancer immunotherapy.

Pictured: 3D illustration of a tumor and its microenvironment/iStock, CIPhoto Nimbus Therapeutics’ small molecule drug candidate NDI-101150 showed strong potential for clinical benefit in patients with advanced solid tumors, the Boston-based biotech announced on Thursday. Results from a Phase I/II study, which will be presented at the American Society of Clinical Oncology annual meeting next week, demonstrated that five out of 30 evaluable patients, or 16.7%, drew clinical benefit from NDI-101150 monotherapy. One patient, who had renal cell carcinoma (RCC), achieved complete response, defined as the disappearance of a tumor and other signs of cancer. Another RCC patient in the dose-expansion cohort showed partial response. Both treatment responders had undergone several prior lines of treatment, including checkpoint inhibitors. Three other patients were able to reach and sustain stable disease for more than six months while undergoing treatment with Nimbus’ drug candidate. These patients had RCC, pancreatic cancer and endometrial cancer, respectively. In terms of safety, the biotech noted that NDI-101150 was “well-tolerated” and that its overall safety profile “remains acceptable.” According to the study’s abstract, 12.8% of treated patients, experienced grade ≥3 treatment-related adverse events. Most common side effects were nausea, vomiting, diarrhea and fatigue. While a 16.7% clinical benefit rate might seem low, Nimbus CMO Nathalie Franchimont in a statement said that the biotech is “encouraged” by these early data which further point to HPK1 “as a differentiated next-generation immunotherapy target” for solid tumors. “NDI-101150 is a potent and highly selective HPK1 inhibitor that has the potential to achieve significant tumor growth inhibition and make a meaningful difference for patients,” Franchimont added. Designed to be orally available, NDI-101150 is a reversible HPK1 inhibitor that works by boosting the activation of T cells, B cells and dendritic cells. The candidate allows the body to “mount a robust anti-tumor response, even under immunosuppressive conditions,” according to Nimbus’ website. NDI-101150 is Nimbus’ only candidate in the clinic and is being developed as a treatment for solid tumors. Aside from its clinical benefit, the Phase I/II study also sought to verify this mechanism of action. Using biopsy samples from an RCC patient on treatment, Nimbus found “increased infiltration” of activated CD8-positive T cells and dendritic cells versus archival biopsies, according to the abstract. A separate portion of the study is testing the combination of NDI-101150 with Merck’s Keytruda (pembrolizumab). Thursday’s readout comes more than a year after Nimbus sold its oral TYK2 inhibitor zasocitinib—along with its wholly owned subsidiary Nimbus Lakshmi—to Takeda for $4 billion upfront, plus potentially $2 billion more contingent on annual sales milestones. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.